A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion

Jyoti Sharma; Ming Du; Eric Wong; Venkateshwar Mutyam; Yao Li; Jianguo Chen; Jamie Wangen; Kari Thrasher; Lianwu Fu; Ning Peng; Liping Tang; Kaimao Liu; Bini Mathew; Robert J. Bostwick; Corinne E. Augelli-Szafran; Hermann Bihler; Feng Liang; Jerome Mahiou; Josef Saltz; Andras Rab; Jeong Hong; Eric J. Sorscher; Eric M. Mendenhall; Candice J. Coppola; Kim M. Keeling; Rachel Green; Martin Mense; Mark J. Suto; Steven M. Rowe; David M. Bedwell

doi:10.1038/s41467-021-24575-x

A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion

Jyoti Sharma, Ming Du, Eric Wong, Venkateshwar Mutyam, Yao Li, Jianguo Chen, Jamie Wangen, Kari Thrasher, Lianwu Fu, Ning Peng, Liping Tang, Kaimao Liu, Bini Mathew, Robert J. Bostwick, Corinne E. Augelli-Szafran, Hermann Bihler, Feng Liang, Jerome Mahiou, Josef Saltz, Andras RabJeong Hong, Eric J. Sorscher, Eric M. Mendenhall, Candice J. Coppola, Kim M. Keeling, Rachel Green, Martin Mense, Mark J. Suto, Steven M. Rowe, David M. Bedwell

Howard Hughes Medical Institution

Research output: Contribution to journal › Article › peer-review

Abstract

Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.

Original language	English (US)
Article number	4358
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24575-x
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Sharma, J., Du, M., Wong, E., Mutyam, V., Li, Y., Chen, J., Wangen, J., Thrasher, K., Fu, L., Peng, N., Tang, L., Liu, K., Mathew, B., Bostwick, R. J., Augelli-Szafran, C. E., Bihler, H., Liang, F., Mahiou, J., Saltz, J., ... Bedwell, D. M. (2021). A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nature communications, 12(1), Article 4358. https://doi.org/10.1038/s41467-021-24575-x

Sharma, J, Du, M, Wong, E, Mutyam, V, Li, Y, Chen, J, Wangen, J, Thrasher, K, Fu, L, Peng, N, Tang, L, Liu, K, Mathew, B, Bostwick, RJ, Augelli-Szafran, CE, Bihler, H, Liang, F, Mahiou, J, Saltz, J, Rab, A, Hong, J, Sorscher, EJ, Mendenhall, EM, Coppola, CJ, Keeling, KM, Green, R, Mense, M, Suto, MJ, Rowe, SM & Bedwell, DM 2021, 'A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion', Nature communications, vol. 12, no. 1, 4358. https://doi.org/10.1038/s41467-021-24575-x

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title = "A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion",

abstract = "Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.",

author = "Jyoti Sharma and Ming Du and Eric Wong and Venkateshwar Mutyam and Yao Li and Jianguo Chen and Jamie Wangen and Kari Thrasher and Lianwu Fu and Ning Peng and Liping Tang and Kaimao Liu and Bini Mathew and Bostwick, {Robert J.} and Augelli-Szafran, {Corinne E.} and Hermann Bihler and Feng Liang and Jerome Mahiou and Josef Saltz and Andras Rab and Jeong Hong and Sorscher, {Eric J.} and Mendenhall, {Eric M.} and Coppola, {Candice J.} and Keeling, {Kim M.} and Rachel Green and Martin Mense and Suto, {Mark J.} and Rowe, {Steven M.} and Bedwell, {David M.}",

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AU - Sharma, Jyoti

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AU - Mutyam, Venkateshwar

AU - Li, Yao

AU - Chen, Jianguo

AU - Wangen, Jamie

AU - Thrasher, Kari

AU - Fu, Lianwu

AU - Peng, Ning

AU - Tang, Liping

AU - Liu, Kaimao

AU - Mathew, Bini

AU - Bostwick, Robert J.

AU - Augelli-Szafran, Corinne E.

AU - Bihler, Hermann

AU - Liang, Feng

AU - Mahiou, Jerome

AU - Saltz, Josef

AU - Rab, Andras

AU - Hong, Jeong

AU - Sorscher, Eric J.

AU - Mendenhall, Eric M.

AU - Coppola, Candice J.

AU - Keeling, Kim M.

AU - Green, Rachel

AU - Mense, Martin

AU - Suto, Mark J.

AU - Rowe, Steven M.

AU - Bedwell, David M.

PY - 2021/12/1

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N2 - Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.

AB - Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.

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A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion

Abstract

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